CLIAMS:
1. An inexpensive and industrially scalable process for preparation of dimethyl fumarate using different catalyst.
2. Catalyst according to claim 1 includes different derivatives of sulfonic acid or polymer promoted ion exchange resins.
3. A process catalyzed by different derivatives of sulfonic acid according to claim 2 comprises:
a) Addition of catalyst to the solution of fumaric acid in anhydrous methanol
at 25-30 0C.;

b) Refluxing mixture of step a) at temperature 65-70 0C for 5-6 hr.;
c) Cooling mixture of step b) at a temperature 20-25 0C with continuous stirring.;
d) Filtration of crystallized product of step c) and washing with cold methanol.;
e) Vacuum drying of final product of step d).
4. A process according to claim 3, wherein the process involves different derivatives of
sulphonic acid of following formula:

Wherein, R group may be alkyl or aryl or which may be substituted. So, catalyst can be selected from methanesulfonic acid, ethanesulfonic acid, proanesulfonic acid, 1-hexanesulfonic acid, 1-heptanesulfonic acid, dodecylbenzenesulfonic acid, 10-camphorsulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid monohydrate
5. A process according to claim 4, wherein the process involves methanesulfonicas catalyst within concentration range of 0.1-0.25%.
6. A process catalyzed by polymer promoted ion exchange resins according to claim 2 comprises:
a) Addition of catalyst to the solution of fumaric acid in anhydrous methanol
at 25-30 0C.;

b) Refluxing mixture of step a) at temperature 65-70 0C for 5-6 hr.;
c) Cooling mixture of step b) at a temperature 50-55 0C.;
d) Filtration of resin catalyst from reaction mixture of step c) under hot condition.;
e) Refluxing clear solution from step d).:
f) Cooling solution of step e) at 25-30 0C.;
g) Filtration of crystallized product of step f) and washing with cold methanol.;
h) Vacuum drying of final product of step g).
7. A process according to claim 7, wherein polymer promoted ion exchange resins can be sulfonated styrene-divinylbenzene types of strong acid ion exchange resins or can be different types of amberlite and Dowex.
8. A process according to claim 8, wherein the process involves Dowex resin as
Catalyst with mesh size of 20-50 mesh
9. A process according to claim 3 and 7, wherein synthesized dimethyl fumarate has yield of more than 75%.

10. Pharmaceutical composition comprises dimethylfumarate prepared by process as claimed in claim 1 and pharmaceutically acceptable excepients.

,TagSPECI:Field of the invention
The present invention relates to process for preparation of dimethyl fumarate and composition containing the same.
Background of invention
Chemically, dimethyl fumarate is the methyl ester of fumaric acid. In the first instance dimethyl fumarate was identified as hypoxic cell radiosensitizer. Later, dimethyl fumarateand ester salts offumaricacid were used for treatment of psoriasis. Severe psoriasis have been treated with fumaric acid salts for a long period of time. Fumaric acid salts also proved to be effective in treatment of multiple sclerosis.Fumaric acid salts have capability of detoxify radicals which releases during the inflammation process. By this mechanism fumaric acid salts are beneficial in protection of nerve and glial cells.
Fumaric acid derivatives are well known in patents U.S. 4,851,439, U.S. 4,959,389, U.S. 6,277,882 for treatment of psoriasis and psoriatic arthritis.U.S.Pat. No. 7,320,999 discloses treatment therapy for autoimmune disease using dialkylfumatare.
U.S.Pat. No.2002/0002306 discloses a method for preparation of dimethyl fumarateby isomerizing maleate using Group VIII element as catalyst with no catalyst residueat the end of reaction. The inventors discloses isomerization of maleate with either base or acid, in case of base complete removal of catalyst is a big hurdle and isomerization by the acid can cause corrosion of reaction vessel.
WO2012170923 discloses a process for preparation of dimethyl fumaratewith low level of dimethyl sulfate impurity using sulfuric acid as an acid catalyst and water sequestrant. The inventors disclosed that equilibrium is shifted towards back to the starting material and results in partial ester hydrolysis with increase in water concentration.
So, to overcome above mentioned problems the present inventors have found the best suitable method for preparation of dimethyl fumarate.
Summary of invention
The inventors have found that the careful selection of catalyst for esterification of fumaric acid gives surprising improvements in the yield of final compound, dimethyl fumarate.
In one general aspect, the present invention provides methods for preparation of dimethylfuamrate using derivatives of sulfonic acid and polymer promoted ion exchange resins as a catalyst. The process for preparation of dimethyl fumarate includes reaction of fumaric acid with methanol in presence of sulfonic acid derivatives or polymer promoted ion exchange resins as a catalyst under reflux.
First method of present invention involves addition of methanesulfonic acid to the solution of fumaric acid in anhydrous methanol at room temperature and then refluxing the reaction mixture to obtain dimethyl fumarate and that gives crude dimethyl fumarate which is further crystallized and dried under vacuum.
Second method of present invention involves addition of Dowex resin to the solution of fumaric acid in anhydrous methanol and refluxing the mixture followed by cooling and filtration processes. This filtrate is further refluxed, cooled and that gives crude dimethyl fumarate which upon further crystallization and vacuum drying gives pure dimethyl fumarate.
In another general aspect present invention comprises synthesized dimethyl fumarate is further used for preparation of composition.
Embodiments of these aspects include one or more following features. Catalysts are different derivatives of sulfonic acid or polymer promoted ion exchange resins.
The dimethyl fumaratesynthesized by this aspect may have a yield of more than 75%.
Detail description of invention
First general aspect present invention provides the preparation of dimethyl fumarate.
First method includes addition of catalyst methanesulfonic acid in concentration range of 0.1-0.25% to the solution of fumaric acid in anhydrous methanol at 25-30 0C. The reaction mixture was refluxed at 65-70 0C for 5-6 h. The reaction mixture was gradually cooled at 20-25 0C after completion of reaction and stirred continuously at the same temperature.

Second step involves filtration of synthesized compound, which is further washed with cold methanol.
Third step of present invention provides a process for drying of the dimethyl fumarate under vacuum at 20-25 0C that gives dried dimethyl fumarate with very good yield.
Here, the catalyst used is of following formula:

Wherein,R group may be alkyl or aryl or which may be substituted. So, catalyst can be selected from methanesulfonic acid, ethanesulfonic acid, proanesulfonic acid, 1-hexanesulfonic acid, 1-heptanesulfonic acid, dodecylbenzenesulfonic acid, 10-camphorsulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid monohydrate.
Catalysts here used are derivatives of sulfonic acid, so being the strong acids they can efficiently prove the function of catalyst. Sulfonic acid derivatives are lipophilic in nature because of this nature they can easily get soluble in organic solvent, so solubility of catalyst is not any hurdle for reaction.
Second method for synthesis of dimethyl fumarateinvolves addition of Dowex resin(20-50 mesh) to the solution of fumaric acid in anhydrous methanol at 25-30 0C. The reaction mixture was then refluxed (65-70 0C) for 5-6 h. After completion of reaction, the mixture was gradually cooled at 50-55 0C.

Second step involves filtration of resin catalyst from reaction mixture under hot condition.
In third step the filtrate is refluxed to get clear solution and this solution was gradually cooled at 25-300C. This filtered clear solution mixture is then kept for crystallization.
Forth step of present invention involves filtration of crystallized product and washing with cold methanol.
Fifth step involves vacuum drying of synthesized compound at 20-25 0C that gives dried dimethyl fumarate with very good yield.
Here,various polymer promoted ion exchange resins such as sulfonated styrene-divinylbenzene types of strong acid ion exchange resins can be used. The resin can be selected from different types of Amberlite and Dowex.
Polymer promoted ion exchange resins contains exchangeable H+cation which makes them very reactive acid.
The main advantages for the use of ion exchange resins are:
1) Non corrosive
2) Easy separation from reaction mixture.
3) Can also be used repeatedly over a prolonged period of time without any difficulty in handling and storage.
Above given both methods for synthesis of dimethyl fumarate does not require any harsh-reaction condition which further protect reaction vessel and yield of final product is not affected.
A second aspect of present invention involves use of synthesized dimethyl fumarate for preparation of pharmaceutical composition or dosage form using pharmaceutically acceptable excepients.